CN111072562A - Tetrahydroisoquinoline derivative and preparation method and application thereof - Google Patents
Tetrahydroisoquinoline derivative and preparation method and application thereof Download PDFInfo
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- CN111072562A CN111072562A CN201911082947.0A CN201911082947A CN111072562A CN 111072562 A CN111072562 A CN 111072562A CN 201911082947 A CN201911082947 A CN 201911082947A CN 111072562 A CN111072562 A CN 111072562A
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- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 35
- 239000001257 hydrogen Substances 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 21
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 16
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 16
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- -1 p-toluenesulfonyl Chemical group 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- SYBXSZMNKDOUCA-UHFFFAOYSA-J rhodium(2+);tetraacetate Chemical compound [Rh+2].[Rh+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O SYBXSZMNKDOUCA-UHFFFAOYSA-J 0.000 claims description 25
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 150000008049 diazo compounds Chemical class 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 2
- 101150003085 Pdcl gene Proteins 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 abstract description 58
- 239000002994 raw material Substances 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 10
- 230000005764 inhibitory process Effects 0.000 abstract description 9
- 230000001093 anti-cancer Effects 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000009982 effect on human Effects 0.000 abstract description 3
- 125000004429 atom Chemical group 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 84
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 51
- 229910052799 carbon Inorganic materials 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 239000012043 crude product Substances 0.000 description 43
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- 238000012360 testing method Methods 0.000 description 25
- 239000000243 solution Substances 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 22
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 22
- 239000011259 mixed solution Substances 0.000 description 22
- 230000002572 peristaltic effect Effects 0.000 description 22
- 239000003208 petroleum Substances 0.000 description 22
- 238000002390 rotary evaporation Methods 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000002156 mixing Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methyl-N-phenylamine Natural products CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 4
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 3
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000003698 anagen phase Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- NLEZSQHAFMZAGU-UHFFFAOYSA-N 2-bromo-5-chloroaniline Chemical compound NC1=CC(Cl)=CC=C1Br NLEZSQHAFMZAGU-UHFFFAOYSA-N 0.000 description 1
- AOPBDRUWRLBSDB-UHFFFAOYSA-N 2-bromoaniline Chemical compound NC1=CC=CC=C1Br AOPBDRUWRLBSDB-UHFFFAOYSA-N 0.000 description 1
- SDYWXFYBZPNOFX-UHFFFAOYSA-N 3,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C(Cl)=C1 SDYWXFYBZPNOFX-UHFFFAOYSA-N 0.000 description 1
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical compound NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a tetrahydroisoquinoline derivative and a preparation method and application thereof. The structure of the compound is shown as a formula I; wherein R is1Is hydrogen, halogen, C1～4Alkyl or C1～4One or more of alkoxy groups; r2Is hydrogen or C1～4An alkyl group; r3Is hydrogen, halogen or C1～4An alkyl group; r4Is hydrogen, benzoyl or p-toluenesulfonyl; r5Is hydrogen or C1～4An alkyl group; r6Is hydrogen or C1～10An alkyl group. The tetrahydroisoquinoline derivative has a novel structure, has a good anticancer cell effect, particularly has a good inhibition effect on human gastric cancer AGS cells, shows a good gastric cancer cell resistance effect, and can be prepared into an anti-gastric cancer medicament for application. At the same time, the user can select the desired position,the preparation method of the compound is simple, the compound which is cheap and easy to obtain is used as a raw material, and the compound has the beneficial effects of mild reaction conditions, few reaction steps, fast reaction, low cost, few generated wastes, simplicity and safety in operation, high atom economy, high selectivity, high yield and the like.
Description
Technical Field
The invention relates to the technical field of pharmaceutical synthesis chemical industry, and more particularly relates to a tetrahydroisoquinoline derivative and a preparation method and application thereof.
Background
The compound with tetrahydroisoquinoline skeleton is widely present in natural products and drug molecules, has various pharmacological effects, such as stronger antihypertensive activity, and also has activity in the aspects of antitumor, antibacterial, antiviral, anti-inflammatory, anticoagulant, bronchodilator, central nervous system action and the like. Based on the unique pharmacological activity, the tetrahydroisoquinoline derivatives occupy an extremely important position in the research and development of new drugs. The synthesis of a plurality of tetrahydroisoquinoline derivatives reported at present has a plurality of defects, most of which have harsh conditions, or the used raw materials are unstable or difficult to obtain, the synthesis process has a plurality of steps, the yield is low, and the operation is very inconvenient.
Therefore, a tetrahydroisoquinoline derivative with a novel structure and a simple preparation method with mild reaction conditions are needed, which is helpful for promoting the research and application of the tetrahydroisoquinoline derivative.
Disclosure of Invention
The purpose of the present invention is to provide a tetrahydroisoquinoline derivative. The tetrahydroisoquinoline derivative has a novel structure, has a good anticancer cell effect, particularly has a good inhibition effect on human gastric cancer AGS cells, shows a good gastric cancer cell resistance effect, and can be prepared into an anti-gastric cancer medicament for application.
Another object of the present invention is to provide a method for preparing the tetrahydroisoquinoline derivative.
The invention also aims to provide application of the tetrahydroisoquinoline derivative.
Still another object of the present invention is to provide an anticancer drug comprising the tetrahydroisoquinoline derivative.
The above object of the present invention is achieved by the following scheme:
a tetrahydroisoquinoline derivative, the structure of said compound is represented by formula I:
wherein R is1Is hydrogen, halogen, C1～4Alkyl or C1～4One or more of alkoxy groups; r2Is hydrogen or C1～4An alkyl group; r3Is hydrogen, halogen or C1～4An alkyl group; r4Is hydrogen, benzoyl or p-toluenesulfonyl; r5Is hydrogen or C1～4An alkyl group; r6Is hydrogen or C1～10An alkyl group.
Preferably, said R is1Is one or more of hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy, ethoxy or propoxy; r2Is hydrogen, methyl or ethyl; r3Is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl or propyl; r5Is hydrofluoro, methyl, ethyl or propyl; r6Is hydrogen, ethyl, tert-butyl or adamantyl.
Preferably, said R is1Is hydrogen, 4-methyl, 4-fluoro, 4-chloro, 4-bromo, 4-iodo, 2-bromo, 2-methoxy, 3-bromo, 2-bromo-4-chloro or 3, 4-dichloro; r2Is hydrogen or methyl; r3Is hydrogen, 5-methyl, 7-chloro or 7-bromo; r4Is benzoyl or p-toluenesulfonyl; r5Is hydrogen or dimethyl; r6Is ethyl, tert-butyl or adamantyl.
Preferably, the tetrahydroisoquinoline derivative is represented by one of the following structures:
the invention also discloses a preparation method of the tetrahydroisoquinoline derivative, wherein the substituted aniline compound shown in the formula 1, the compound shown in the formula 2 and the compound shown in the formula 3 react at room temperature in the presence of a catalyst to prepare the compound shown in the formula I;
preferably, the catalyst is [ PdCl (η)3-C3H5)]2、Cu(OTf)2CuOTf, AgOTf, CuI or Rh2(OAc)4(ii) a More preferably, the reaction catalyst is Rh2(OAc)4。
Preferably, the temperature of the reaction is 0-45 ℃; more preferably, the reaction temperature is 25 ℃.
Preferably, the reaction time is 1.0-3.0 h; more preferably, the reaction time is 3 h.
Preferably, the reaction molar ratio of the substituted aniline compound shown in the formula 1, the compound shown in the formula 2, the diazo compound shown in the formula 3 and the catalyst is 1.5-2.0: 1.0-1.5: 2.0-2.5: 0.02-0.1; more preferably, the reaction molar ratio is 1.5:1.0:2.5: 0.05.
Preferably, the reaction is carried out in an organic solvent of dichloromethane, 1, 2-dichloroethane, ethyl acetate, chloroform, tetrahydrofuran, toluene or methyl tert-butyl ether; more preferably, the reaction is carried out in methyl tert-butyl ether.
Preferably, the specific process of the reaction is as follows: dissolving the substituted aniline compound shown in the formula 1, the compound shown in the formula 2 and a catalyst in an organic solvent, and then dropwise adding the organic solvent in which the diazo compound shown in the formula 3 is dissolved for reaction.
The application of the tetrahydroisoquinoline derivative or the isomer thereof or the pharmaceutically acceptable salt thereof in the preparation of the anti-cancer medicament is also within the protection scope of the invention.
Preferably, the anticancer drug is a drug against human gastric cancer cells.
More preferably, the anticancer drug is a drug inhibiting gastric cancer AGS cells.
The invention also protects an anticancer drug containing the tetrahydroisoquinoline derivative or the isomer thereof or the pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention has the following beneficial effects:
the tetrahydroisoquinoline derivative has a novel structure, has a good anticancer cell effect, particularly has a good inhibition effect on human gastric cancer AGS cells, shows a good gastric cancer cell resistance effect, and can be prepared into an anti-gastric cancer medicament for application.
Meanwhile, the preparation method of the compound is simple, the compound which is cheap and easy to obtain is used as a raw material, and the compound has the beneficial effects of mild reaction conditions, few reaction steps, quick reaction, low cost, less generated waste, simplicity and safety in operation, high atom economy, high selectivity, high yield and the like.
The compound is simple to prepare, low in cost, has a good inhibition effect on gastric cancer cells, and has a great application prospect in the aspect of preparing gastric cancer treatment medicines.
Drawings
FIG. 1 shows the product obtained in example 11H NMR scheme.
FIG. 2 shows the product obtained in example 113Schematic C NMR.
FIG. 3 shows the product obtained in example 21H NMR scheme.
FIG. 4 shows the product obtained in example 213Schematic C NMR.
FIG. 5 shows the product obtained in example 31H NMR scheme.
FIG. 6 shows the product obtained in example 313Schematic C NMR.
FIG. 7 shows the product obtained in example 41H NMR scheme.
FIG. 8 shows the product obtained in example 413Schematic C NMR.
FIG. 9 shows the results of example 111H NMR scheme.
FIG. 10 shows the product obtained in example 11Of an object13Schematic C NMR.
FIG. 11 shows the product obtained in example 131H NMR scheme.
FIG. 12 shows the results obtained in example 1313Schematic C NMR.
FIG. 13 shows the results of example 141H NMR scheme.
FIG. 14 shows the results of example 1413Schematic C NMR.
FIG. 15 shows the results of example 191H NMR scheme.
FIG. 16 shows the results of example 1913Schematic C NMR.
FIG. 17 shows the results of example 201H NMR scheme.
FIG. 18 shows the results of example 2013Schematic C NMR.
FIG. 19 shows the results of example 211H NMR scheme.
FIG. 20 shows the results of example 2113Schematic C NMR.
FIG. 21 shows the results of example 221H NMR scheme.
FIG. 22 shows a photograph of a product obtained in example 2213Schematic C NMR.
FIG. 23 shows the results of a preliminary screening of compounds for inhibition of AGS cell proliferation.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1
Mixing C, N-cyclomethine (0.2mmol) and p-toluidine(0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 62%, dr value: 85:15.
1H NMR(400MHz,CDCl3)δ7.80–7.72(m,2H),7.47(d,J＝6.8Hz,1H),7.43–7.33(m,2H),7.30–7.23(m,1H),7.19–7.09(m,2H),7.06(d,J＝6.5Hz,1H),6.86(d,J＝7.4Hz,2H),6.41(d,J＝7.5Hz,2H),5.17–5.05(m,1H),4.37–4.24(m,1H),3.92–3.68(m,2H),3.62–3.43(m,1H),3.38–3.26(m,1H),3.26–3.13(m,1H),2.80–2.61(m,1H),2.15(s,3H),0.94(t,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ174.2,166.0,145.1,135.5,135.0,133.0,132.0,129.5,128.7,128.5,127.0,126.8,126.53,126.45,113.8,66.0,62.8,61.3,51.0,29.7,20.4,13.9.
Example 2
Mixing C, N-cyclomethine imine (0.2mmol), para-fluoroaniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 73%, dr value: 84:16.
1H NMR(500MHz,Acetone)δ9.03(s,1H),7.87(d,J＝7.6Hz,2H),7.58–7.51(m,1H),7.51–7.43(m,3H),7.27–7.19(m,1H),7.19–7.09(m,2H),6.82–6.72(m,2H),6.59–6.51(m,2H),5.95(d,J＝9.8Hz,1H),5.11–5.00(m,1H),4.54–4.44(m,1H),3.92–3.81(m,1H),3.77–3.66(m,1H),3.44–3.37(m,1H),3.37–3.31(m,1H),3.29–3.18(m,1H),2.80–2.75(m,1H),0.92(t,J＝7.1Hz,3H).19F NMR(470MHz,CDCl3)δ-127.74(s).13C NMR(125MHz,Acetone)δ172.6,165.6,155.3(d,J＝232.1Hz),145.08(d,J＝1.4Hz),136.1,135.9,133.7,131.5,128.34,128.28,127.3,126.5,126.4,126.2,114.9,114.8,114.3,114.2,66.0,62.3,60.4,51.7,29.8,13.3.
Example 3
Mixing C, N-cycloformimine (0.2mmol), p-chloroaniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 85%, dr value: 86:14.
1H NMR(400MHz,CDCl3)δ7.74(d,J＝7.5Hz,2H),7.54–7.38(m,4H),7.29(d,J＝7.3Hz,1H),7.22–7.13(m,2H),7.09(d,J＝7.1Hz,1H),6.99(d,J＝8.5Hz,2H),6.56–6.34(m,2H),5.58–5.35(m,1H),5.17–4.97(m,1H),4.37–4.21(m,1H),3.92–3.70(m,2H),3.54–3.41(m,1H),3.39–3.30(m,1H),3.28–3.18(m,1H),2.81–2.67(m,1H),0.94(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ173.7,166.0,146.1,135.3,134.7,132.8,132.1,128.8,128.7,128.6,127.03,126.96,126.6,126.4,122.2,114.8,66.2,62.5,61.5,51.4,29.7,13.8.
Example 4
Mixing C, N-cycloformimine (0.2mmol), p-bromoaniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 65%, dr value: 87:13.
1H NMR(500MHz,CDCl3)δ7.74(d,J＝7.2Hz,2H),7.54–7.50(m,1H),7.43(dd,J＝15.3,8.0Hz,3H),7.29(d,J＝7.2Hz,1H),7.22–7.08(m,5H),6.47–6.31(m,2H),5.62–5.39(m,1H),5.15–4.97(m,1H),4.33–4.23(m,1H),3.91–3.74(m,2H),3.54–3.43(m,1H),3.39–3.31(m,1H),3.27–3.19(m,1H),2.81–2.67(m,1H),0.94(t,J＝6.8Hz,3H).13C NMR(125MHz,Acetone)δ172.2,165.7,147.8,135.84,135.80,133.6,131.6,131.3,128.4,128.3,127.3,126.6,126.4,126.3,115.2,107.5,65.9,61.5,60.6,51.7,29.8,13.3.
Example 5
Mixing C, N-cycloformimine (0.2mmol), p-iodoaniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 81%, dr value: 86:14.
1H NMR(500MHz,CDCl3)δ7.80–7.68(m,2H),7.57–7.46(m,2H),7.45–7.36(m,2H),7.33–7.23(m,3H),7.22–7.12(m,2H),7.12–7.05(m,1H),6.41–6.17(m,2H),5.78–5.35(m,1H),5.23–4.95(m,1H),4.38–4.18(m,1H),3.94–3.69(m,2H),3.60–3.41(m,1H),3.38–3.28(m,1H),3.27–3.14(m,1H),2.84–2.64(m,1H),1.03–0.85(m,3H).13C NMR(125MHz,CDCl3)δ173.6,166.0,147.2,137.5,135.3,134.7,132.8,132.2,128.7,128.6,127.04,126.99,126.6,126.4,115.9,78.3,66.1,62.1,61.5,51.4,29.7,13.9.
Example 6
Mixing C, N-cycloformimine (0.2mmol), o-bromoaniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 75%, dr value: 88:12.
1H NMR(400MHz,CDCl3)δ7.88–7.68(m,3H),7.52–7.25(m,5H),7.11(d,J＝22.4Hz,3H),7.04–6.93(m,1H),6.58–6.39(m,1H),6.35–6.15(m,1H),5.99–5.73(m,1H),5.57–5.33(m,1H),4.40–4.20(m,1H),3.99–3.70(m,3H),3.48–3.20(m,2H),2.86–2.63(m,1H),1.11–0.89(m,3H).13C NMR(100MHz,CDCl3)δ173.4,166.0,144.2,135.7,135.1,132.9,132.5,132.1,128.7,128.4,128.2,127.0,126.9,126.51,126.49,118.1,111.7,110.4,65.2,62.3,61.5,50.9,30.6,14.0.
Example 7
Mixing C, N-cycloformimine (0.2mmol), o-anisidine (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 52%, dr value: 80:20.
1H NMR(500MHz,CDCl3)δ7.92(s,1H),7.77–7.72(m,2H),7.52–7.45(m,1H),7.42–7.36(m,2H),7.27(d,J＝7.5Hz,1H),7.17–7.08(m,2H),7.05(d,J＝7.3Hz,1H),6.72–6.66(m,2H),6.61–6.55(m,1H),6.27(dd,J＝8.2,1.3Hz,1H),5.56(s,1H),5.37–5.30(m,1H),z4.37–4.27(m,1H),3.97–3.87(m,1H),3.86–3.73(m,5H),3.35–3.28(m,1H),3.22(ddd,J＝15.8,11.6,4.5Hz,1H),2.79–2.70(m,1H),0.99(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ173.9,166.0,147.2,137.2,135.7,135.2,133.1,131.9,128.6,128.3,126.9,126.74,126.70,126.3,121.1,117.1,110.5,110.1,65.3,62.2,61.2,55.7,50.4,30.2,14.0.
Example 8
Mixing C, N-cyclomethine imine (0.2mmol), m-bromoaniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 64%, dr value: 86:14。
1H NMR(500MHz,CDCl3)δ7.79–7.68(m,2H),7.46(d,J＝37.8Hz,4H),7.33–7.27(m,1H),7.18(d,J＝17.1Hz,2H),7.13–7.06(m,1H),6.94–6.84(m,1H),6.77–6.67(m,1H),6.67–6.58(m,1H),6.50–6.36(m,1H),5.67–5.45(m,1H),5.18–4.99(m,1H),4.30(s,1H),3.91–3.71(m,2H),3.56–3.42(m,1H),3.40–3.31(m,1H),3.29–3.18(m,1H),2.82–2.67(m,1H),1.02–0.88(m,3H).13C NMR(125MHz,CDCl3)δ173.6,166.0,148.8,135.3,134.6,132.7,132.2,130.2,128.7,128.6,127.1,127.0,126.6,126.4,122.9,120.4,116.2,112.4,66.1,62.0,61.5,51.4,29.8,13.9.
example 9
Mixing C, N-cycloformimine (0.2mmol), 2-bromo-5-chloroaniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 62%, dr value: 82:18.
1H NMR(500MHz,CDCl3)δ7.75(d,J＝7.6Hz,2H),7.63(s,1H),7.54–7.50(m,1H),7.46–7.41(m,2H),7.31(d,J＝7.6Hz,1H),7.25–7.19(m,2H),7.17–7.13(m,1H),7.12–7.07(m,1H),6.45(dd,J＝8.4,1.9Hz,1H),6.18(d,J＝1.6Hz,1H),5.96(d,J＝8.7Hz,1H),5.46–5.39(m,1H),4.26–4.21(m,1H),3.94–3.78(m,3H),3.39–3.31(m,2H),2.79–2.73(m,1H),1.03(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ172.8,166.0,145.2,135.8,134.8,133.9,133.0,132.7,132.1,128.7,128.5,127.01,126.96,126.7,126.5,117.8,111.6,108.1,65.3,62.1,61.7,51.0,30.5,14.0.
Example 10
Mixing C, N-cyclomethine imine (0.2mmol), 3, 4-dichloroaniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 54%, dr value: 83:17.
1H NMR(500MHz,CDCl3)δ7.77–7.71(m,2H),7.55–7.51(m,1H),7.47–7.38(m,3H),7.30(d,J＝7.5Hz,1H),7.24–7.16(m,2H),7.12–7.08(m,1H),7.06(d,J＝8.7Hz,1H),6.59–6.52(m,1H),6.43–6.33(m,1H),5.67(d,J＝6.0Hz,1H),5.11–4.99(m,1H),4.31–4.23(m,1H),3.90–3.75(m,2H),3.49–3.41(m,1H),3.38–3.32(m,1H),3.28–3.20(m,1H),2.80–2.71(m,1H),0.95(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ173.3,166.1,147.2,135.3,134.5,132.7,132.4,132.2,130.3,128.7,128.6,127.2,127.0,126.7,126.3,119.9,114.7,113.4,66.2,62.2,61.6,51.6,29.7,13.8.
Example 11
Mixing C, N-cycloformimine (0.2mmol), aniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specific temperature (25 ℃), and then a solution containing diazo (0.5mmol) of methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude productA compound (I) is provided. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 81%, dr value: 89:11.
1H NMR(500MHz,CDCl3)δ7.75(d,J＝6.9Hz,2H),7.52(dd,J＝15.8,8.2Hz,2H),7.46–7.36(m,2H),7.30(d,J＝7.1Hz,1H),7.21–7.12(m,2H),7.06(dd,J＝15.8,7.6Hz,3H),6.67–6.57(m,1H),6.58–6.42(m,2H),5.49–5.23(m,1H),5.21–5.04(m,1H),4.41–4.28(m,1H),3.94–3.73(m,2H),3.65–3.47(m,1H),3.41–3.30(m,1H),3.29–3.18(m,1H),2.83–2.67(m,1H),0.94(t,J＝6.5Hz,3H).13C NMR(125MHz,CDCl3)δ174.1,165.9,147.4,135.4,134.9,132.9,132.1,129.0,128.7,128.5,127.0,126.9,126.52,126.50,117.7,113.7,66.0,62.4,61.3,51.2,29.8,13.9.
Example 12
Mixing C, N-cycloformimine (0.2mmol), N-methylaniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 36%, dr value: 95:5.
1H NMR(500MHz,CDCl3)δ7.63(d,J＝6.8Hz,2H),7.55(s,1H),7.50–7.44(m,1H),7.40–7.35(m,2H),7.25–7.20(m,3H),7.16(d,J＝7.9Hz,1H),7.15–7.07(m,2H),6.91(d,J＝7.3Hz,2H),6.80–6.74(m,1H),4.86(d,J＝8.5Hz,1H),4.67–4.52(m,1H),4.03–3.94(m,2H),3.33–3.19(m,5H),3.06–2.97(m,1H),2.96–2.86(m,1H),1.05(t,J＝7.0Hz,3H).13CNMR(100MHz,CDCl3)δ170.5,165.4,150.3,134.0,133.6,132.9,131.7,129.3,129.2,128.62,128.58,127.7,127.0,126.3,118.2,114.2,66.4,63.0,60.8,47.3,33.8,25.2,14.0.
Example 13
Substituted C, N-cycloformimine (0.2mmol), aniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 80%, dr value: 89:11.
1H NMR(500MHz,CDCl3)δ7.74(d,J＝6.3Hz,2H),7.55–7.36(m,4H),7.19–7.13(m,1H),7.06(dd,J＝21.2,14.7Hz,4H),6.66–6.58(m,1H),6.52(d,J＝6.7Hz,2H),5.52–5.30(m,1H),5.13–4.97(m,1H),4.38–4.27(m,1H),3.92–3.72(m,2H),3.59–3.44(m,1H),3.44–3.35(m,1H),3.05–2.89(m,1H),2.82–2.72(m,1H),2.23(s,3H),1.02–0.85(m,3H).13C NMR(100MHz,CDCl3)δ174.1,165.9,147.5,135.8,134.5,133.9,133.0,132.0,129.0,128.7,128.5,127.0,126.2,124.4,117.7,113.7,66.2,62.6,61.3,50.7,26.3,19.4,13.9.
Example 14
Substituted C, N-cycloformimine (0.2mmol), aniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) of methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours until C, N-cycloformiminium was obtainedAfter the reaction is finished, the solvent is removed by reduced pressure rotary evaporation to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 72%, dr value: 85:15.
1H NMR(500MHz,CDCl3)δ7.74(d,J＝7.2Hz,2H),7.59(s,1H),7.52–7.46(m,1H),7.40(t,J＝7.0Hz,2H),7.11–7.02(m,3H),7.00–6.91(m,2H),6.66–6.59(m,1H),6.51(d,J＝7.6Hz,2H),5.39(br,1H),5.18–4.93(m,1H),4.36–4.26(m,1H),3.96–3.65(m,2H),3.61–3.40(m,1H),3.37–3.27(m,1H),3.22–3.11(m,1H),2.79–2.60(m,1H),2.29(s,3H),0.94(t,J＝6.8Hz,3H).13C NMR(125MHz,CDCl3)δ174.2,165.9,147.5,136.0,134.6,133.0,132.3,132.0,129.0,128.7,128.3,127.9,127.0,117.6,113.6,66.0,62.3,61.3,51.2,29.3,21.2,13.9.
Example 15
Substituted C, N-cycloformimine (0.2mmol), aniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 65%, dr value: 80:20.
1H NMR(500MHz,CDCl3)δ7.81–7.70(m,2H),7.70–7.62(m,1H),7.54–7.47(m,1H),7.45–7.35(m,2H),7.34–7.26(m,1H),7.16–7.04(m,3H),7.03–6.97(m,1H),6.68–6.60(m,1H),6.59–6.38(m,2H),5.28(br,1H),5.18–5.03(m,1H),4.39–4.19(m,1H),3.95–3.72(m,2H),3.68–3.48(m,1H),3.38–3.25(m,1H),3.22–3.09(m,1H),2.78–2.62(m,1H),1.04–0.87(m,3H).13C NMR(125MHz,CDCl3)δ173.8,166.0,147.1,137.0,134.1,132.7,132.2,132.1,129.8,129.1,128.7,127.2,127.0,126.5,118.0,113.8,65.5,62.3,61.5,50.8,29.4,13.9.
Example 16
Substituted C, N-cycloformimine (0.2mmol), aniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 56%, dr value: 79:21.
1H NMR(500MHz,CDCl3)δ7.74(d,J＝7.1Hz,2H),7.60(s,1H),7.54–7.49(m,1H),7.46–7.40(m,3H),7.27–7.24(m,1H),7.12–7.03(m,2H),6.96(d,J＝7.9Hz,1H),6.67–6.63(m,1H),6.52(d,J＝7.5Hz,2H),5.26(br,1H),5.18–5.07(m,1H),4.32–4.24(m,1H),3.97–3.71(m,2H),3.60(t,J＝9.5Hz,1H),3.39–3.27(m,1H),3.14(t,J＝12.9Hz,1H),2.77–2.64(m,1H),0.97(t,J＝6.6Hz,3H).13C NMR(125MHz,CDCl3)δ173.7,166.0,147.1,137.3,134.5,132.7,132.2,130.1,130.0,129.4,129.1,128.7,126.9,120.1,118.0,113.8,65.4,62.3,61.5,50.7,29.5,13.9.
Example 17
Mixing C, N-cycloformimine (0.2mmol), p-chloroaniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in the flask 2.After stirring at a specific temperature (25 ℃) in a test tube of 0mL of methyl tert-butyl ether, a solution of diazo (0.5mmol) dissolved in methyl tert-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, after the reaction of C, N-cycloformimine was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 65%, dr value: 77:23.
1H NMR(500MHz,CDCl3)δ7.86(d,J＝6.8Hz,2H),7.34(d,J＝6.6Hz,2H),7.20–7.13(m,2H),6.52(d,J＝7.5Hz,2H),6.10(br,1H),5.16–4.93(m,1H),4.41(d,J＝5.0Hz,1H),4.22–4.10(m,2H),4.06–3.99(m,1H),2.99–2.90(m,1H),2.80–2.73(m,1H),2.71–2.62(m,2H),2.45(s,3H),1.19–1.08(m,3H).13C NMR(125MHz,CDCl3)δ172.2,145.7,144.4,135.7,133.9,132.0,129.8,129.1,129.0,128.2,127.8,127.7,126.4,122.8,114.7,67.1,62.1,61.6,48.3,21.7,13.9.
Example 18
Mixing C, N-cycloformimine (0.2mmol), aniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 66%, dr value: 45:55.
1H NMR(500MHz,CDCl3)δ7.90–7.89(m,1H),7.82–7.69(m,2H),7.56–7.38(m,4H),7.19–7.07(m,5H),7.07–6.94(m,3H),6.66(s,1H),4.98–4.74(m,2H),4.19–3.98(m,2H),3.77–3.64(m,1H),3.41–3.24(m,1H),3.11–2.97(m,1H),2.95–2.82(m,1H),2.52–2.36(m,1H),1.28–1.19(m,6H),0.81–0.69(m,3H).13C NMR(125MHz,CDCl3)δ172.9,165.8,146.1,138.8,134.4,133.5,131.8,128.71,128.67,128.2,127.8,127.2,127.1,125.8,117.6,117.3,75.0,68.8,61.3,51.8,29.9,27.7,19.3,18.2,14.1.
Example 19
Mixing C, N-cycloformimine (0.2mmol), aniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 66%, dr value: 90:10.
1H NMR(500MHz,CDCl3)δ7.76(d,J＝7.1Hz,2H),7.69(s,1H),7.51–7.46(m,1H),7.43–7.36(m,2H),7.30(d,J＝7.1Hz,1H),7.21–7.13(m,2H),7.10–7.02(m,3H),6.64–6.58(m,1H),6.53(d,J＝7.3Hz,2H),5.56–5.38(m,1H),5.07–4.94(m,1H),4.24–4.15(m,1H),3.61(t,J＝9.7Hz,1H),3.39–3.32(m,1H),3.19(t,J＝11.5Hz,1H),2.82–2.70(m,1H),1.17(s,9H).13C NMR(125MHz,CDCl3)δ172.9,166.0,147.5,135.5,135.3,133.1,132.0,129.0,128.6,128.3,127.2,127.0,126.9,126.5,117.5,113.6,82.0,65.6,63.4,50.8,29.5,27.8.
Example 20
Mixing C, N-cycloformimine (0.2mmol), aniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃ C.),then adding a solution dissolved with diazo (0.5mmol) methyl tert-butyl ether (1.0mL) into the mixed solution through a peristaltic pump, adding the solution for one hour, continuing to react for two hours, and removing the solvent through reduced pressure rotary evaporation after the C, N-cycloimine reaction is finished to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 72%, dr value: 90:10.
1H NMR(500MHz,CDCl3)δ7.84(s,1H),7.77(d,J＝7.5Hz,2H),7.50–7.45(m,1H),7.42–7.35(m,2H),7.27(d,J＝7.5Hz,1H),7.20–7.11(m,2H),7.08–7.02(m,3H),6.64–6.58(m,1H),6.52(d,J＝7.7Hz,2H),5.44(br,1H),5.09–4.96(m,1H),4.22–4.13(m,1H),3.69–3.53(m,1H),3.38–3.30(m,1H),3.24–3.15(m,1H),2.77–2.66(m,1H),1.91–1.85(m,3H),1.75(dd,J＝23.3,11.2Hz,6H),1.44(dd,J＝31.7,12.0Hz,6H).13C NMR(125MHz,CDCl3)δ172.7,166.1,147.6,135.6,135.4,133.3,131.9,129.0,128.5,128.3,127.3,126.9,126.8,126.4,117.5,113.7,82.0,65.7,63.4,50.9,41.1,35.9,30.7,29.7.
Example 21
Substituted C, N-cycloformimine (0.2mmol), aniline (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 73%, dr value: 94:6.
1H NMR(500MHz,CDCl3)δ7.79–7.71(m,2H),7.70–7.63(m,1H),7.49–7.44(m,1H),7.43–7.34(m,2H),7.14–6.98(m,5H),6.63–6.57(m,1H),6.57–6.45(m,2H),5.50–5.36(m,1H),4.95(d,J＝10.4Hz,1H),4.20–4.07(m,1H),3.62–3.49(m,1H),3.43–3.33(m,1H),2.97–2.86(m,1H),2.80–2.71(m,1H),2.20(s,3H),1.92–1.86(m,3H),1.80–1.71(m,6H),1.52–1.38(m,6H).13C NMR(125MHz,CDCl3)δ172.6,166.0,147.6,135.6,135.2,133.8,133.3,131.9,128.9,128.5,128.3,127.3,126.1,124.8,117.5,113.7,82.0,65.9,63.5,50.4,41.1,35.9,30.7,26.2,19.4.
Example 22
Mixing C, N-cyclomethine (0.2mmol), p-toluidine (0.3mmol) and Rh2(OAc)4(5.0 mol%) was dissolved in a test tube containing 2.0mL of methyl t-butyl ether, stirred at a specified temperature (25 ℃), and then a solution containing diazo (0.5mmol) dissolved in methyl t-butyl ether (1.0mL) was added to the above mixed solution by a peristaltic pump for one hour, and the reaction was continued for two hours, and after the reaction of C, N-cyclomethine was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:6) to give a pair of diastereomers, in total yield: 53%, dr value: 87:13.
1H NMR(400MHz,CDCl3)δ7.82–7.76(m,2H),7.50–7.44(m,1H),7.44–7.34(m,2H),7.32–7.25(m,1H),7.21–7.10(m,2H),7.10–7.00(m,1H),6.87(d,J＝6.4Hz,2H),6.61–6.30(m,2H),5.09–4.97(m,1H),4.18–4.07(m,1H),3.78–3.57(m,1H),3.42–3.28(m,1H),3.26–3.11(m,1H),2.85–2.62(m,1H),2.16(s,3H),1.94–1.85(m,3H),1.85–1.68(m,6H),1.56–1.36(m,6H).13C NMR(100MHz,CDCl3)δ172.8,166.0,145.1,135.6,135.4,133.3,131.9,129.5,128.5,128.3,127.2,127.0,126.8,126.7,126.4,113.7,81.9,65.7,63.7,50.6,41.1,35.9,30.7,29.7,20.4.
The hydrogen and carbon spectra of some of the compounds prepared in examples 1 to 22 are shown in fig. 1 to 22.
Example 23
And (3) activity test:
fractions from examples 1 to 22 were each dissolved in DMSO and further diluted in culture medium. The final concentration of DMSO is not more than 0.1% (v/v).
The test cells were human gastric cancer AGS cells, which were inoculated in a medium containing 10% serum and 1% penicillin-streptomycin solution at 37 ℃ in 5% CO2In the incubator, the cells were passaged every 2 days, and cells in the logarithmic growth phase were taken out for the experiment.
1. Taking cells in logarithmic growth phase, and adjusting cell suspension to 7 x 10 with prepared fresh culture medium3To 96 well plates, 150. mu.L per well volume, 5% CO2After incubation at 37 ℃ for 24 hours, the product of the above example was added at a concentration of 5.0. mu.M in a volume of 10. mu.L and incubated, and after 72 hours, 10. mu.L of CCK8 was added to each well and incubated at 37 ℃ with 5% CO2After 1 hour in the incubator, absorbance at 450nm was measured by a multifunctional microplate reader (FLUOstar Promega).
A Control group and a blank group are simultaneously set, wherein the Control group contains AGS cells and DMSO but no compound, and the blank group only contains DMSO but no cells. The results for each experimental condition were averaged over 3 replicate wells in one experiment.
Cell viability (%) [ a (medicated) -a (blank) ]/[ a (Control group) -a (blank) ] × 100, inhibition rate ═ 1-cell viability (%).
The results of preliminary screening using cell viability values are shown in FIG. 23.
2. Determination of IC by the CCK8 method50The specific process is as follows: taking cells in logarithmic growth phase, and adjusting cell suspension to 7 x 10 with prepared fresh culture medium3To 96 well plates, 150. mu.L per well volume, 5% CO2After incubation at 37 ℃ for 24 hours, the product was added at a concentration of 20, 10, 5, 2.5, 1.25, 0.625. mu.M in a volume of 10. mu.L and incubated, after 72 hours, CCK8 was added in a volume of 10. mu.L per well and incubated at 37 ℃ with 5% CO2After 1 hour in the incubator, absorbance at 450nm was measured in a multifunctional microplate reader (FLUOstarrPromega).
A Control group and a blank group are simultaneously set, wherein the Control group contains AGS cells and DMSO but no compound, and the blank group only contains DMSO but no cells. The results for each experimental condition were averaged over 3 replicate wells in one experiment.
Cell viability (%) [ a (medicated) -a (blank) ]/[ a (Control group) -a (blank) ] × 100, inhibition rate ═ 1-cell viability (%).
For each sample, the average cell growth was expressed as a percentage of the average control cell growth, and IC was calculated using GraphPad prism750(concentration of drug required to reduce cell growth to 50% of Control).
Table 1 is the IC of the Compounds50And (5) value detection results.
IC of Compounds of Table 1 for inhibition of AGS cell proliferation50Value of
| Sample number | Sample numbering | Molecular Formula (Formula) | Molecular Weight (MW) | IC50(uM) |
| 1 | 4a | C27H29N3O3 | 443.22 | 2.19 |
| 2 | 4m | C27H29N3O3 | 443.22 | 3.29 |
| 3 | 4u | C35H39N3O3 | 549.30 | 2.59 |
| 4 | 4v | C35H39N3O3 | 549.30 | 4.77 |
As shown in the test results in the table, the compounds all have good inhibition effect on AGS cells, and the IC of the compounds50The values are all lower than 5 mu M, and the results show that the compound prepared by the invention can be developed and prepared into a medicament for treating gastric cancer.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A tetrahydroisoquinoline derivative, wherein the structure of said compound is represented by formula I:
wherein R is1Is hydrogen, halogen, C1～4Alkyl or C1～4One or more of alkoxy groups; r2Is hydrogen or C1～4An alkyl group; r3Is hydrogen, halogen or C1～4An alkyl group; r4Is hydrogen, benzoyl or p-toluenesulfonyl; r5Is hydrogen or C1～4An alkyl group; r6Is hydrogen or C1～10An alkyl group.
2. The tetrahydroisoquinoline derivative according to claim 1, wherein R is1Is one or more of hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy, ethoxy or propoxy; r2Is hydrogen, methyl or ethyl; r3Is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl or propyl; r5Is hydrofluoro, methyl, ethyl or propyl; r6Is hydrogen, ethyl, tert-butyl or adamantyl.
3. The tetrahydroisoquinoline derivative according to claim 2, wherein R is1Is hydrogen, 4-methyl, 4-fluoro, 4-chloro, 4-bromo, 4-iodo, 2-bromo, 2-methoxy, 3-bromo, 2-bromo-4-chloro or 3, 4-dichloro; r2Is hydrogen or methyl; r3Is hydrogen, 5-methyl, 7-chloro or 7-bromo; r4Is benzoyl or p-toluenesulfonyl; r5Is hydrogen or dimethyl; r6Is ethyl, tert-butyl or adamantyl.
4. The tetrahydroisoquinoline derivative according to claim 3, wherein said tetrahydroisoquinoline derivative has one of the following structures:
5. the method for producing the tetrahydroisoquinoline derivative according to any one of claims 1 to 4, wherein the substituted aniline compound represented by formula 1, the compound represented by formula 2, and the diazo compound represented by formula 3 are reacted in the presence of a catalyst to produce the compound represented by formula I;
6. the method for producing the tetrahydroisoquinoline derivative according to claim 5, wherein the catalyst is [ PdCl (η)3-C3H5)]2、Cu(OTf)2CuOTf, AgOTf, CuI or Rh2(OAc)4。
7. The method for producing a tetrahydroisoquinoline derivative according to claim 5, wherein the molar ratio of the substituted aniline compound represented by formula 1, the compound represented by formula 2, the diazo compound represented by formula 3, and the catalyst is 1.5 to 2.0:1.0 to 1.5:2.0 to 2.5:0.02 to 0.1.
8. The use of the tetrahydroisoquinoline derivative or isomer thereof or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for the preparation of an anticancer agent.
9. The use of claim 8, wherein the anti-cancer drug is a drug against human gastric cancer cells.
10. An anticancer agent comprising the tetrahydroisoquinoline derivative or isomer thereof according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
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